title: Development of a gene/drug dual delivery system for brain tumor therapy: potent inhibition via RNA interference and synergistic effects.
abstract: Malignant brain tumors are characterized by three major physiological processes: proliferation, angiogenesis, and invasion. Traditional cytotoxic chemotherapies (e.g. Paclitaxel) control the tumor by blocking growth and proliferation mechanisms, but leave angiogenesis and invasion unchecked. We identified Matrix metalloproteinase-2 (MMP-2), an essential proteinase regulating brain tumor invasion and angiogenesis, as one of the therapeutic target. A designer RNAi plasmid was developed, and complexed with the gene carrier polyethylenimine (PEI), in an effort to specifically suppress MMP-2 expression in tumor cells. The gene and a cytotoxic drug Paclitaxel were then dual-encapsulated in PLGA based submicron implants to achieve a sustained release of both agents. Potent inhibition effects on MMP-2 mRNA and protein expression, in vitro cell angiogenesis and invasion were demonstrated both on the PEI/DNA nanoparticles alone, and on the PEI/DNA nanoparticles embedded in microfibers. Most importantly, through in vivo test on intracranial xenograft tumor model in BALB/c nude mice, it was proved that the gene/drug dual delivery microfibers are able to impose significant tumor regression compared with single drug delivery microfibers and commercial drug treatment, showing evidence for synergistic therapeutic efficacy.
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117576, Singapore.
authors.forename: Chenlu
authors.initials: C
authors.lastname: Lei
authors.forename: Yanna
authors.initials: Y
authors.lastname: Cui
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.forename: Pierce Kah-Hoe
authors.initials: PK
authors.lastname: Chow
authors.forename: Chi-Hwa
authors.initials: CH
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D020007:Implants, Experimental; D008163:Luminescent Measurements; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D009389:Neovascularization, Pathologic / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D011094:Polyethyleneimine / Q000737:chemistry; D034622:RNA Interference / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011094:Polyethyleneimine; D004247:DNA; D020778:Matrix Metalloproteinase 2
keywords: Drug/gene delivery; Intracranial glioblastoma; MMPs; Microfiber; RNA interference